EP0572494B1 - Zusammensetzung zur verwendung in der transdermalen verabreichung - Google Patents

Zusammensetzung zur verwendung in der transdermalen verabreichung Download PDF

Info

Publication number
EP0572494B1
EP0572494B1 EP92905485A EP92905485A EP0572494B1 EP 0572494 B1 EP0572494 B1 EP 0572494B1 EP 92905485 A EP92905485 A EP 92905485A EP 92905485 A EP92905485 A EP 92905485A EP 0572494 B1 EP0572494 B1 EP 0572494B1
Authority
EP
European Patent Office
Prior art keywords
active agent
composition according
biologically active
transdermal composition
transdermal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP92905485A
Other languages
English (en)
French (fr)
Other versions
EP0572494A4 (en
EP0572494A1 (de
Inventor
Reginald Morton Taylor
David John Wilson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Commonwealth Scientific and Industrial Research Organization CSIRO
Original Assignee
Commonwealth Scientific and Industrial Research Organization CSIRO
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/795,499 external-priority patent/US5308621A/en
Application filed by Commonwealth Scientific and Industrial Research Organization CSIRO filed Critical Commonwealth Scientific and Industrial Research Organization CSIRO
Publication of EP0572494A1 publication Critical patent/EP0572494A1/de
Publication of EP0572494A4 publication Critical patent/EP0572494A4/en
Application granted granted Critical
Publication of EP0572494B1 publication Critical patent/EP0572494B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention relates to compositions incorporating biologically active agents and to methods of preparing such compositions.
  • the invention also provides methods of treatment using such compositions.
  • Australian patent application number 33006/89 by Medvet Science Pty Ltd describes a topical anti-inflammatory or anti-irritant composition which includes a zinc salt of one or more compounds selected from unsaturated fatty acids, polyunsaturated fatty acids and cyclic derivatives thereof and aspirin in a pharmaceutically acceptable vehicle.
  • the zinc salts used in this composition are described as being generally crystalline solids or greasy pastes (depending upon the degree of saturation) and should be stored at -70°C in a CO 2 or N 2 atmosphere for optimum stability.
  • Suitable vehicles/carriers for the composition described in AU-A-33006/89 include ethanol, dimethylsulphoxide (DMSO), isopropanol, glycerol, propylene glycol, dimethylacetamide and mixtures thereof.
  • the compositions are formulated by dissolving or dispersing the dry zinc salt in DMSO and subsequently diluting with glycerol.
  • AU-A-33006/89 does not describe how the aspirin is incorporated into the composition.
  • United States patent no. 4555524 by Gruber et al describes a transdermal medicament for the delivery of 2-(4-isobutylphenyl)-propionic acid (commonly known as ibuprofen) to a patient.
  • the medicament comprises a base capable of dissolving ibuprofen, which base contains 30-50 parts by weight C 6-12 carboxylic acid triglyceride, 4-10 parts by weight glycerol monostearate - polyoxyethylene stearate mixture and 2-10 parts by weight polyoxyethylene fatty acid ester.
  • ibuprofen 2-(4-isobutylphenyl)-propionic acid
  • United States patent no. 4511563 to Schmolka discloses analgesic gels that include 5-15 parts of an analgesic compound, 10-40 parts of a non-ionic surfactant, 5-40 parts glycerin and 40-70 parts water.
  • the surfactants are essential to produce the required product in the form of a gel.
  • United States patent no. 4665063 by Bar-Shalom describes a method for treating skin disorders by applying a composition comprising acetyl salicyclic acid and a suitable carrier.
  • the patent does not describe how the compositions are manufactured; the only requirement being that the acetyl salicyclic acid is dissolved in the carrier.
  • Ascorbic acid is a biologically active agent which has properties which make the formulation of compositions for transdermal delivery extremely difficult.
  • Ascorbic acid is notoriously unstable and although it is soluble in water its propensity to oxidise in aqueous solution and/or degrade due to attack by water itself make it desirable to minimise the use of water.
  • solubility of ascorbic acid in non-aqueous solvents is relatively poor. Consequently despite numerous attempts to produce stable compositions for transdermal delivery concentrations of ascorbic acid in commercially useful formulations have generally been limited to less than 10% ascorbic acid.
  • compositions comprising higher concentration of ascorbic acid using water and a co-solvent such as an alcohol or glycol.
  • a co-solvent such as an alcohol or glycol.
  • these inventions rely on presence of water to solubilise sufficient ascorbic acid to provide an effective composition.
  • EP-A-0 156 080 describes a conformable percutaneous absorption device for delivering a drug by absorption through the skin or mucosa.
  • EP-A-0 151 953 describes a pharmaceutical composition for topical administration consisting of two liquid phases designed to be admixed in situ or prior to use.
  • WO 92/08445 describes a palatable liquid therapeutic microemulsion wherein a drug dissolved in propylene glycol is dispersed in fatty ester.
  • the rate of transdermal delivery of biologically active compounds present in a carrier at a level above their solubility limit in the carrier, when applied directly to the skin, can be increased and controlled by having at least a substantial proportion of the active compounds present in the carrier in the form of fine particles.
  • the invention provides a composition for transdermal administration of a biologically active agent comprising said biologically active agent and a pharmaceutically acceptable carrier wherein said pharmaceutically acceptable carrier comprises at least one liquid that does not undergo significant reaction with the biologically active agent, wherein the biologically active agent is present at a concentration above its solubility limit in said carrier at ambient conditions and wherein there are sufficient fine particles of said agent dispersed through said carrier to substantially facilitate the transdermal transfer capacity of said composition.
  • biologically active agent shall be taken to include pharmaceuticals, therapeutic agents and prophylactic agents.
  • composition may include a single biologically active agent or two or more compatible biologically active agents. It is therefore to be understood that the term “biologically active agent” also encompasses two or more biologically active agents.
  • Said biologically active agent will be present as a saturated or super saturated solution in said carrier.
  • at least 60% of the solid particles of active agent are sized less than 20 microns. More preferably, at least 30% of the solid particles are sized less than 10 microns. Even more preferably, at least 60% of the particles are sized less than 10 microns. In a most preferred embodiment, at least 30%, even more preferably at least 60% of the particles are sized less than 5 microns.
  • compositions would be formulated in such a way as to ensure that at least 30% of the biologically active agent present in the composition would be delivered transdermally within 150 hours, preferably 48 hours, more preferably 3 hours of direct application of the composition to the skin.
  • a portion for example, 5 to 80% of the particles, may be extremely fine, for example less than 5 microns, and preferably in the range of 2 to 5 microns, in order to give a very high sequentiale range of transdermal effect.
  • a second portion of the particles (for example 5 to 94%) may be of a larger size, for example less than 20 microns and preferably in the range of from 5 to 20 microns, and a third portion, say 1 to 40%, may be larger than 20 microns, to ensure an ongoining slow increase of activity over a period.
  • a portion of the particles may be encapsulated in an outer layer which is adapted to delay the activity of the encapsulated particles until the outer layer dissolves or is in some other way dissipated by any means such as melting by body heat being dissolved by fluids on skin or in a second component added before applcation etc.
  • compositions may include stabilisers to maintain stability at normal storage temperatures particularly room temperature, or they may be formulated in such a way as to ensure stability at such temperature.
  • composition may further comprise one or more of a stabiliser, a dispersing agent, an emulsifier, a thickening agent and other ointment bases.
  • the size of said particles is graded to ensure an effective rate of transdermal release over an extended period of time.
  • said period is a least 3 hours.
  • said period is at least 48 hours.
  • said period is at least 150 hours.
  • this invention comprises formulating an active agent, preferably ibuprofen, aspirin, captopril or ascorbic acid, in a carrier so as to provide a saturated solution of the said active agent and wherein at least 60% of the particulate active agent is present in the form of solid particles sized less than 20 microns.
  • an active agent preferably ibuprofen, aspirin, captopril or ascorbic acid
  • the particle size of the particles was determined by microscopic examination. It should be assumed that the particles are of a constant thickness. The surface area of each visible particle face should be determined, and the particle size calculated by calculating the square root of the visible surface area of each particle. This value should then be taken to the average length of side and hence size of that particle.
  • the biologically active agent used in the composition is advantageously a pharmaceutically active agent.
  • suitable pharmaceutically active agents include aspirin, 2-(4-isobutylphenyl)-propionic acid (ibuprofen), ascorbic acid and captopril. It will be appreciated that the above list is not exhaustive and that the invention also encompasses the use of pharmaceutically active agents other than those specifically mentioned.
  • composition according to the present invention include but are not limited to the following:
  • Examples of pharmaceutically acceptable carriers include those selected from the group consisting of water, polyhydric alcohols including alkylene glycols, (particularly propylene glycol) and glycerol; alcohols such as ethanol and isopropanol; polyalkylene glycols such as polyethylene glycol and polypropylene glycol; other ointment bases such as petroleum jelly, lanolin, dimethylformamide, ethylene glycol, tetrahydrofurfuryl alcohol, cyclohexane, cyclohexanone, acetone, ethylether, N-dodecylazocyclo-heptan-2-one, methyldecylsulfoxide, dimethylacetamide and diethylfoluamide; and mixtures thereof.
  • polyhydric alcohols including alkylene glycols, (particularly propylene glycol) and glycerol
  • alcohols such as ethanol and isopropanol
  • polyalkylene glycols such as polyethylene glyco
  • the biologically active agent is ascorbic acid
  • said ascorbic acid is present in an amount of from 20 to 45% by weight of the composition and the pharmaceutically acceptable carrier is selected from the group consisting of glycerol, propylene glycol, polyethylene glycol.
  • composition further includes aspirin or ascorbic acid or mixtures thereof.
  • the biologically active agent is ibuprofen
  • said ibuprofen is present in an amount of from 15 to 35% by weight of the composition.
  • the preferred carriers are inert liquids, that is, they do not undergo any significant reaction with the active agent.
  • the above list is not exclusive as the present invention also encompasses the use of pharmaceutically acceptable carriers other than those specifically mentioned.
  • Glycerol, propylene glycol and polyethylene glycol are preferred and glycerol has been found to be particularly useful.
  • the active agent is ascorbic acid then preferably the carrier contains little or no water and preferably contains less than about 0.5% by weight water.
  • compositions according to the present invention have been found to be suitable for supplying or delivering a biologically active agent for therapeutic and/or prophylactic purposes in both human and veterinary applications.
  • the invention involves use of the hereinbefore defined composition in treatment of a human or animal disorder.
  • the invention provides a method for delivering a biologically active agent transdermally to a body which comprises applying a composition according to the invention to the skin of the body.
  • the present invention includes a method for the treatment and/or preventoin of a disorder in a human or animal which comprises administering an effective amount of a composition described herein to the human or animal.
  • the invention involves use of a composition as hereinbefore defined in treatment of a localised inflammation wherein said active agent is an anti-inflammatory such as ibuprofen.
  • compositions of the present invention have been found to be particularly efficacious in delivering the biologically active agent by transdermal migration following topical application, and this is the preferred route for administering the compositions.
  • the compositoins may also be administered orally or by parenteral or subdermal deposition.
  • the present invention also includes methods for producing the compositions described herein.
  • the present invention includes a method for producing a composition, which composition comprises a pharmaceutically acceptable carrier and a biologically active agent, which method comprises:
  • any crystals of biologically active agent that form are predominantly sized less than 20 ⁇ m.
  • the method of the present invention may be carried out by heating the pharmaceutically acceptable carrier to the desired temperature and then adding the biologically active agent.
  • a mixture of the organic active agent and the carrier may be produced at room temperature and subsequently heated to dissolve substantially all of the biologically active agent.
  • the mixture is stirred whilst it is being heated.
  • the mixture may be heated by conventional means or by microwave radiation, with microwave heating being preferred.
  • the mixture may be heated to a temperature in the range of from 60 to 170°C and more preferably 100 to 130°C.
  • the minimum temperature required to obtain complete dissolution of the particles is preferably used, particularly in the case of active agents and/or carriers which are liable to decompose at excessive temperatures.
  • the temperature required to be used will vary according to the solubility of the biologically active agent in the carrier and the degradation temperature of the biologically active agent.
  • the cooling step of the present invention may be used to control the particle size of any particles of biologically active agent that form.
  • the cooling step may involve rapidly cooling the heated mixture to ambient or below ambient temperature. This quick cooling (or "shock cooling") of the mixture can result in the formation of small particles of biologically active agent. Large particles generally do not grow because of rapid cooling and resultant increase in viscosity largely prevents diffusion of biologically active agent in solution to the particles that may have nucleated.
  • Quick cooling may be achieved by placing the mixture in an ice bath.
  • An alternative cooling step involves allowing the mixture to slowly cool.
  • This cooling method requires that the mixture be viscous.
  • the high viscosity of the mixture will largely prevent diffusion or reduce the rate of diffusion of dissolved biologically active agent to any particles of biologically active agent that may nucleate. The result is particles of biologically active agent that are predominantly sized less than 20 micrometres.
  • the viscosity of the mixture may be increased by adding viscosity modifying agents to the mixture.
  • the pharmaceutically acceptable carrier may constitute the viscosity modifying agent.
  • suitable viscosity modifying agents include polyethylene glycol and ointments based thereon, petroleum jelly and paraffin wax.
  • present invention is produced by heating the carrier and the biologically active agent to melt or liquefy the active agent.
  • the resulting liquid (or, in some cases, immiscible liquids) are then stirred to effectively disperse the molten active agent throughout the carrier.
  • the mixture is then cooled whilst maintaining stirring to produce a composition according to the present invention.
  • the temperature required to produce one or more liquid phases is above the degradation temperature of either the active agent or the carrier, another method of preparation will have to be used.
  • particles of biologically active agents in the chosen sizes may be prepared, (for example by grinding) and subsequently mixed with a pharmaceutically acceptable carrier to produce a composition in accordance with the invention.
  • a composition containing ibuprofen was prepared by adding 20.6g ibuprofen to a heated 130°C solution consisting of 26.2 g glycerol, 21.6g propylene glycol and 2.5g polyethylene glycol (20000). The solution was stirred at this temperature until it became clear and then transferred into a vessel controlled at 4°C in which it was stirred until a creamy paste formed. The paste was allowed to remain at this low temperature for a further 15 minutes and then stirred again to form a viscous paste.
  • the particle size of the ibuprofen crystallites precipitated during the cooling and stirring of the above formulation was compared with that of the unreacted ibuprofen powder.
  • the respective particle sizes were determined by microscopic examination. It was assumed that the crystals were of a constant thickness. The surface area of each crystal was then determined, and the particle size calculated by calculating the square root of the measured surface area. This value was then taken to be the length of side. The total area of the counted particles was measured and the sum of the areas of the different size ranges estimated as a percentage of the total. The results were: Ibuprofen/Glycerol Composition of the Present Invention Size Range Percent of Particles in Size Range ⁇ 2 ⁇ m 0.35 2-5 ⁇ m 32.4 5-10 ⁇ m 42 10-15 ⁇ m 23
  • This example demonstrates the preparation of a composition containing Ibuprofen.
  • Ibuprofen 40 parts by weight of Ibuprofen is added to 93 parts by weight of propylene glycol heated to 130°C. The solution was stirred until clear and then quickly cooled under solidified carbon dioxide with stirring. This produces a soft white paste.
  • Ibuprofen 20.6g was dissolved in 45 g propylene glycol heated to between 120 to 130°C. A clear solution was obtained. This solution was stirred while cooling to obtain a creamy white formulation with small (less than 10 microns) ibuprofen particles.
  • Ibuprofen 20.6 g Ibuprofen was dissolved in 55g propylene glycol at 120°C. The resulting clear solution was added to a jacketed container surrounded by water at 6°C. Upon stirring, a creamy white formulation with small particles (less than 10 microns) of ibuprofen was formed.
  • Ibuprofen was dissolved in a heated mixture containing 40g propylene glycol and 30g glycerol. The clear solution was allowed to cool and was shaken for 5 minutes to give a creamy white material with particles of ibuprofen less than 10 microns.
  • Ibuprofen was added to 70g glycerol heated to 120 C.
  • the ibuprofen melted and formed an immiscible top layer.
  • the mixture was stirred vigorously while cooling to give a white cream.
  • Small crystals of ibuprofen (less than 5 microns) were present, but aggregates of the small crystals were also formed.
  • the sample was ground by a mortar and pestle to remove the aggregates.
  • the transdermal transfer of this formulation was tested in a Franz cell and compared against a commercially available ibuprofen cream. After 22 hours, the compositon according to the example had delivered 306 micrograms of the ibuprofen across the skin membrane for the Franz cell. In the same time, the commercially available ibuprofen cream delivered 170 microgroms ibuprofen.
  • compositions of ibuprofen in glycerol exhibit an abilty to alleviate pain with topical application.
  • the rebound of pain after about 3-4 hours indicates an analgesic effect resulting possibly from the anti-inflammatory action of the ibuprofen.
  • This example demonstrates the preparation of a composition containing aspirin.
  • a composition containing ascorbic acid was prepared by the method of the invention. 35.2g ascorbic acid was dissolved in a heated solution containing 43.2g propylene glycol and 5g polyethylene glycol (20000) at 140°C. The solution was cooled to about 100°C and then rapidly cooled in a jacketed vessel to 4°C with stirring, until the material became a very viscous cream. It was bottled and a sample examined by optical microscopy.
  • the comparative mixture had ascorbic acid crystals that were approximately square shaped (equidimensional).
  • the ascorbic acid crystals of the composition of the invention contained crystals of varied shape, with equidimensional crystals being the most common.
  • the particle size of the crystals were determined by microscopic examination. It was assumed that the crystals were of a constant thickness. The surface area of each crystal was then determined, and the particle size calculated by calculating the square root of the measured surface area. This value was then taken to be the length of side. The total area of the counted particles was measured and the sum of the areas of the different size ranges estimated as a percentage of the total. The results were: Ascorbic Acid - Carrier Composition According to the Present Invention Size range. Percentage Particles in Size range ⁇ 2 ⁇ m 12.7 2-5 ⁇ m 42.5 5-10 ⁇ m 45.8 Unformulated Ascorbic Acid: Comparative Example Size range. Percentage Particles in Size range 10-20 ⁇ m 0.36 20-50 ⁇ m 0.57 50-100 ⁇ m 2.7 >100 ⁇ m 96
  • composition of the present invention has ascorbic acid particles with a much smaller particle size than that of the comparative example.
  • compositions comprising ascorbic acid and glycerol were produced.
  • Composition A was produced by adding 3 parts ascorbic acid by weight to 7 parts glycerol by weight. The mixture was heated to 120-130°C to dissolve the ascorbic acid. The heated mixture was quenched by adding dry ice. Ascorbic acid particles present in composition A were predominantly in the size range of 2-10 microns.
  • Composition B was prepared by mixing C 14 labelled ascorbic acid with unlabelled ascorbic acid.
  • the ascorbic acid was dissolved and recrystallised to ensure adequate mixing of the labelled and unlabelled ascorbic acid.
  • the recrystallised ascorbic acid was broken up on a mortar and pestle and sieved through a nylon sieve. Particles in the range of 50-100 microns were collected and mixed with glycerol in a weight ratio of 3 to 7. No attempt was made to heat this mixture.
  • Composition A was applied to two laboratory rats and ascorbic acid levels in blood and uring were measured over a six hour period and the mean of the two rats determined at each time period.
  • composition B The same tests were conducted on two other laboratory rats using composition B. The results were plotted to show the variation of ascorbic acid match and are shown in the attached drawings.
  • 35.2g ascorbic acid was added to a ternary mixture containing 43.2g propylene glycol, 52.4g glycerol and 5g polyethylene glycol heated to 140°C.
  • the solution was cooled to about 100°C and then added to a jacketed vessel cooled with water at 4°C.
  • the solution was stirred with a propeller stirrer until it became too viscous, after which the stirrer was raised.
  • the composition adhering to the stirrer bladed showed some very small crystals.
  • the product was kept chilled in the jacketted vessel for 1.5 hours before storing at room temperature.
  • Figure 3 shows that the variation over 22 hours in the permeation of the two size ranges of ibuprofen through the two skin sections following the application of approximately equal amounts of the respective formulations to similar areas.
  • the animals were placed in metabolism cages and the urinary ibuprofin monitored.
  • a rat was anesthetized and clipped and shaved in the dorsal area just below the neck. Labelled ibuprofen in polypropylene glycol was applied to the shaved area. The area of application was then covered witha plastic cover. The amount of ibuprofen excreted in the urine was determined and the results shown in Figure 5.
  • Example 6 The method of Example 6 was repeated using 14 C labelled ascorbic acid of corresponding particle sizes.
  • Figure 2 shows the variation over six hours in permeation of the two size ranges of ascorbic acid through the two skin sections following application of approximately equal amounts of respective formulations to similar areas.
  • a mixture containing 18.24g propylene glycol, 22.1g glycerol and 10.08g polyethylene glycol (20000) was heated to 100°C. 10g ascorbic acid and 10g aspirin were added and stirred until dissolved. Dry ice was added to the solution, which was stirred until cold. A white viscous cream was obtained.
  • Captopril was dissovled in heated glycerol and cooled in the refrigerator. After cooling to 4° C, the solution which was stirred and a white cream contining particles sized predominantly less than 5 microns was obtained.
  • a composition was prepared by adding 30g ibuprofen to a heated mixture containing 40g propylene glycol and 30g glycerol.
  • the ibuprofen dissolved in the propylene glycol.
  • the solution was cooled slightly and divided into two parts. One part was shaken by hand, the other part was shaken by mixer. A white creamy material formed in both.
  • the machine shaken part had very small particles of ibuprofen.
  • the other sample was transferred to a beaker and reheated to give a clear solution.
  • the beaker was placed in a sub-zero environment where the solution became viscous but remained clear.
  • the paste was then stirred until a white creamy thin paste formed. This contained very fine particles (essentially less than 5 microns).
  • composition according to the present invention is cleraly superior to the commercially available cream.
  • a composition was prepared by adding 30g ibuprofen to 70g heated glycerol.
  • the ibuprofen melted and formed a separate liquid layer on top of the glycerol.
  • the mixture was stirred and subjected to ultrasonics while cooling. Some creamy material formed, but this contained many hard aggregates. Microscopic examination showed that the un-agglomerated particles were small.
  • a sub-sample was ground in a mortar until a consistent, non-particulate cream was formed. 21.6mg of this material was applied to the skin of a Franz cell. 44.6mg of a commercially available ibuprofen cream was applied to another Franz cell. The results are shown in Figure 7. As can be seen, the commercially available cream had an initially higher rate of transdermal release, but there was a cross-over at about 15 hours, after which the composition according to the present invention was clearly superior.
  • Examples 19 and 20 have led the inventors to postulate that the transdermal transfer characteristics of the inventive conditions may be improved when a carrier that at least partially dissolves the biologically active agent is used. Comparing the transdermal transfer characteristics of the compositions of the invention from Examples 19 and 20, it can be shown that the composition of Example 19, which contained propylene glycol (in which ibuprofen does dissolve to a certain extent) and superior transdermal transfer characteristics to the composition of Example 20, which used glycerol as a carrier (ibuprofen being substantially insoluble in glycerol). However, both compositions showed transdermal transfer of the active agent.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (26)

  1. Transdermale Zusammensetzung in Form einer Creme oder einer Salbe zur Verabreichung eines biologisch aktiven Wirkstoffs, die einen biologisch aktiven Wirkstoff sowie einen pharmazeutisch zulässigen Träger aufweist, bei der der genannte biologisch aktive Wirkstoff in einer Konzentration oberhalb seiner Löslichkeitsgrenze in dem genannten Träger bei Umgebungsbedingungen vorliegt und bei der der biologisch aktive Wirkstoff in Form von feinen Festoffteilchen vorliegt, die im ganzen Träger dispergiert sind, und wobei wenigstens 60% der Feststoffteilchen eine Größe von weniger als 20µm aufweisen.
  2. Transdermale Zusammensetzung nach Anspruch 1, bei der wenigstens 30% der Feststoffteilchen des Wirkstoffs eine Größe von weniger als 10µm aufweisen.
  3. Transdermale Zusammensetzung nach Anspruch 1, bei der wenigstens 30% der Feststoffteilchen des Wirkstoffs eine Größe von weniger als 5µm aufweisen.
  4. Transdermale Zusammensetzung nach Anspruch 1, bei der wenigstens 60% der Feststoffteilchen des Wirkstoffs eine Größe von weniger als 10µm aufweisen.
  5. Transdermale Zusammensetzung nach Anspruch 1, bei der wenigstens 60% der Feststoffteilchen des Wirkstoffs eine Größe von weniger als 5µm aufweisen.
  6. Transdermale Zusammensetzung nach irgendeinem der vorausgehenden Ansprüche, bei der der pharmazeutisch zulässige Träger wenigstens eine Flüssigkeit umfaßt, die mit dem biologisch aktiven Wirkstoff keine nennenswerte Reaktion eingeht.
  7. Transdermale Zusammensetzung nach irgendeinem der vorausgehenden Ansprüche, bei der der pharmazeutisch zulässige Träger ausgewählt ist aus Glycerol, Propylenglykol, Polypropylenglykol, anderen mehrwertigen Alkoholen, Vaselin, Lanolin, Dimethylformamid, Ethylenglykol, Tetrahydrofurfurylalkohol, Cyclohexan, Aceton, Ethylether, N-Dodecylazocycloheptan-2-on, Methyldecylsulfoxid, Dimethylacetamid und Diethyltoluamid und Mischungen davon.
  8. Transdermale Zusammensetzung nach irgendeinem der vorausgehenden Ansprüche, bei der der biologisch aktive Wirkstoff ausgewählt ist aus Ascorbinsäure, nicht steroidalen entzündungshemmenden Mitteln, Antiasthmamitteln, Reisekrankheitsmitteln, Arzneimitteln, die zur Behandlung von dermatologischen Erkrankungen verwendet werden, Opiaten oder schmerzlindernden Arzneimitteln, Narkotikums-Agonisten, Narkotikums-Antagonisten, Krampfmitteln, Sedativa, hypnotischen Mitteln, Lokalanästhetika, Wachstumsfaktoren, Insulin, Streptokinase, Peptiden, Antivirusmitteln, AZT, Kontrazeptiva, Calciumkanal-Blockern, blutdrucksenkenden Arzneimitteln, Prazosin, Propranolol, Guanethidin, Clonidin, ACE-Inhibitoren und Captopril.
  9. Transdermale Zusammensetzung nach Anspruch 8, bei der der genannte biologisch aktive Wirkstoff Ascorbinsäure ist und die Ascorbinsäure in einer Menge von 20 bis 45 Gew.-% der Zusammensetzung vorliegt und bei der der pharmazeutisch zulässige Träger ausgewählt ist aus Glycerol, Propylenglykol und Polyethylenglykol und Mischungen davon.
  10. Transdermale Zusammensetzung nach Anspruch 8, bei der der genannte biologisch aktive Wirkstoff ein nicht steroidales entzündungshemmendes Mittel ist, das ausgewählt ist aus Aspirin, Salicylaten, Indomethacin, Aryl- und Heteroarylalkansäuren, Ibuprofen, Ketoprofen und Flubiprofen.
  11. Transdermale Zusammensetzung nach Anspruch 10, bei der die genannte Zusammensetzung außerdem Ascorbinsäure enthält.
  12. Transdermale Zusammensetzung nach Anspruch 10 oder Anspruch 11, bei der der biologisch aktive Wirkstoff Ibuprofen ist, das in einer Menge von 15 bis 35 Gew.-% der Zusammensetzung vorliegt.
  13. Transdermale Zusammensetzung nach Anspruch 8, bei der das Antiasthmamittel Theophyllin ist.
  14. Transdermale Zusammensetzung nach Anspruch 8 , bei der das Reisekrankheitsmittel Scopolamin ist.
  15. Transdermale Zusammensetzung nach Anspruch 8, bei der der genannte biologisch aktive Wirkstoff, der zur Behandlung von dermatologischen Erkrankungen verwendet wird, ausgewählt ist aus Retinoiden, Mystedin und Minomycin.
  16. Transdermale Zusammensetzung nach Anspruch 8, bei der das genannte Opiat oder schmerzlindernde Mittel ausgewählt ist aus Morphin, Methadon oder Kodein.
  17. Transdermale Zusammensetzung nach Anspruch 8, bei der der biologisch aktive Wirkstoff Benzodiazepine sind.
  18. Transdermale Zusammensetzung nach irgendeinem der vorausgehenden Ansprüche, bei der die Zusammensetzung zwei oder mehr biologisch aktive Wirkstoffe enthält.
  19. Transdermale Zusammensetzung nach irgendeinem der vorausgehenden Ansprüche, bei der die genannte Zusammensetzung außerdem einen oder mehrere von einem Stabilisator, einem Dispergiermittel, einem Emulgator, einem Verdickungsmittel und anderen Salbengrundlagen enthält.
  20. Transdermale Zusammensetzung nach irgendeinem der vorausgehenden Ansprüche, bei der die Größe der genannten Teilchen abgestuft ist, um einen wirksamen Grad der transdermalen Freigabe über einen ausgedehnten Zeitraum sicherzustellen.
  21. Transdermale Zusammensetzung nach Anspruch 20, bei der der genannte Zeitruam wenigstens drei Stunden beträgt.
  22. Transdermale Zusammensetzung nach Anspruch 20, bei der der genannte Zeitraum wenigstens 48 Stunden beträgt.
  23. Transdermale Zusammensetzung nach Anspruch 20, bei der der genannte Zeitraum wenigstens 150 Stunden beträgt.
  24. Transdermale Zusammensetzung nach irgendeinem der Ansprüche 20 bis 23, bei der wenigstens 30% des biologisch aktiven Wirkstoffs innerhalb des genannten Zeitraums zugeführt werden.
  25. Transdermale Zusammensetzung nach irgendeinem der vorausgehenden Ansprüche, bei der 5% bis 80% der Teilchen kleiner sind als 5µm, 5% bis 94% der Teilchen zwischen 5 und 20µm liegen und 1% bis 40% der Teilchen größer sind als 20µm.
  26. Verfahren zur Herstellung einer Zusammensetzung nach irgendeinem der vorausgehenden Ansprüche, wobei das Verfahren umfaßt:
    a) Auflösen einer Menge des genannten biologisch aktiven Wirkstoffs in dem pharmazeutisch zulässigen Träger bei einer erhöhten Temperatur, wobei die genannte Menge des biologisch aktiven Wirkstoffs höher ist als die Löslichkeitsgrenze in dem Träger bei Umgebungsbedingungen und
    b) Abkühlen der Mischung, um Teilchen des biologisch aktiven Wirkstoffs zu erzeugen, die ausreichend fein sind, um einen wirksamen Grad des transdermalen Transfers des genannten biologisch aktiven Wirkstoffs zu ermöglichen, wenn die genannte Zusammensetzung topisch angewendet wird.
EP92905485A 1991-02-18 1992-02-18 Zusammensetzung zur verwendung in der transdermalen verabreichung Expired - Lifetime EP0572494B1 (de)

Applications Claiming Priority (15)

Application Number Priority Date Filing Date Title
AU4651/91 1991-02-18
AUPK465191 1991-02-18
AU465191 1991-02-18
AU7848/91 1991-08-19
AU7846/91 1991-08-19
AU784891 1991-08-19
AU7847/91 1991-08-19
AUPK784791 1991-08-19
AU784691 1991-08-19
AUPK784691 1991-08-19
AU784791 1991-08-19
AUPK784891 1991-08-19
US795499 1991-11-21
US07/795,499 US5308621A (en) 1991-02-18 1991-11-21 Ascorbic acid composition and transdermal administration method
PCT/AU1992/000058 WO1992014442A1 (en) 1991-02-18 1992-02-18 Composition for use in transdermal administration

Publications (3)

Publication Number Publication Date
EP0572494A1 EP0572494A1 (de) 1993-12-08
EP0572494A4 EP0572494A4 (en) 1996-05-29
EP0572494B1 true EP0572494B1 (de) 1999-08-25

Family

ID=27507420

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92905485A Expired - Lifetime EP0572494B1 (de) 1991-02-18 1992-02-18 Zusammensetzung zur verwendung in der transdermalen verabreichung

Country Status (7)

Country Link
EP (1) EP0572494B1 (de)
JP (1) JPH06508100A (de)
AT (1) ATE183639T1 (de)
AU (1) AU668679B2 (de)
CA (1) CA2103725C (de)
DE (1) DE69229857T2 (de)
WO (1) WO1992014442A1 (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11110093B2 (en) 2005-09-30 2021-09-07 Indivior Uk Limited Sustained release small molecule drug formulation
US11712475B2 (en) 2007-05-25 2023-08-01 Indivior Uk Limited Sustained delivery formulations of risperidone compound

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3123193A (en) * 1991-12-13 1993-07-19 G.D. Searle & Co. Transdermal azidothymidine
DE4329446A1 (de) * 1993-09-01 1995-03-02 Basf Ag Verfahren zur Herstellung von feinteiligen Farb- oder Wirkstoffzubereitungen
DE4332093C2 (de) * 1993-09-22 1995-07-13 Lohmann Therapie Syst Lts Transdermales therapeutisches System mit dem Wirkstoff Acetylsalicylsäure und Verfahren zu seiner Herstellung
US6103267A (en) * 1998-07-27 2000-08-15 Sunsmart, Inc. Stabilized ascorbic acid, composition, and method of use
JP2003040763A (ja) * 2001-05-23 2003-02-13 Taisho Pharmaceut Co Ltd 多価アルコール含有軟膏剤基剤
DE10237057A1 (de) * 2002-08-09 2004-03-25 Grünenthal GmbH Opioid-Rezeptor-Antagonisten in Pflasterformulierungen
DE10261696A1 (de) 2002-12-30 2004-07-15 Schwarz Pharma Ag Vorrichtung zur transdermalen Verabreichung von Rotigotin-Base
US9272044B2 (en) 2010-06-08 2016-03-01 Indivior Uk Limited Injectable flowable composition buprenorphine
GB2481017B (en) 2010-06-08 2015-01-07 Rb Pharmaceuticals Ltd Microparticle buprenorphine suspension
GB201404139D0 (en) 2014-03-10 2014-04-23 Rb Pharmaceuticals Ltd Sustained release buprenorphine solution formulations

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR751951A (fr) * 1933-03-02 1933-09-13 Procédé d'hydrophilisation des corps gras
FR948326A (fr) * 1947-06-24 1949-07-28 Brillantine à base d'hormones
US4156736A (en) * 1976-05-28 1979-05-29 Sanol Schwarz-Monheim Gmbh Supersaturated isosorbide dinitrate solution, process for its production and its use
GB8401965D0 (en) * 1984-01-25 1984-02-29 Beecham Group Plc Composition
GB8629639D0 (en) * 1986-12-11 1987-01-21 Beecham Group Plc Composition & method
ATE42901T1 (de) * 1984-03-05 1989-05-15 Nitto Denko Corp Haftendes arzneimittelpraeparat fuer perkutane absorption.
US4573995A (en) * 1984-10-09 1986-03-04 Alza Corporation Transdermal therapeutic systems for the administration of naloxone, naltrexone and nalbuphine
JPH066534B2 (ja) * 1986-10-09 1994-01-26 積水化学工業株式会社 経皮吸収貼付剤
GB8629640D0 (en) * 1986-12-11 1987-01-21 Beecham Group Plc Composition & method
US5110606A (en) * 1990-11-13 1992-05-05 Affinity Biotech, Inc. Non-aqueous microemulsions for drug delivery

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Dorland's Illustrated Medical Dictionary,1985,"cream","ointment" *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11110093B2 (en) 2005-09-30 2021-09-07 Indivior Uk Limited Sustained release small molecule drug formulation
US11712475B2 (en) 2007-05-25 2023-08-01 Indivior Uk Limited Sustained delivery formulations of risperidone compound

Also Published As

Publication number Publication date
AU668679B2 (en) 1996-05-16
WO1992014442A1 (en) 1992-09-03
AU1272392A (en) 1992-09-15
EP0572494A4 (en) 1996-05-29
CA2103725A1 (en) 1992-08-19
CA2103725C (en) 2002-06-04
ATE183639T1 (de) 1999-09-15
EP0572494A1 (de) 1993-12-08
DE69229857T2 (de) 2000-04-20
DE69229857D1 (de) 1999-09-30
JPH06508100A (ja) 1994-09-14

Similar Documents

Publication Publication Date Title
EP0572494B1 (de) Zusammensetzung zur verwendung in der transdermalen verabreichung
CN1080561C (zh) 外用抗炎剂
PT833611E (pt) Composicao que compreendendo um agente activo dissolvido num veiculo formador de vidro e processo para a sua preparacao
AU617570B2 (en) Microgranulates comprising a saturated fatty acid triglyceride and an active substance, and topical pharmaceutical compositions containing such microgranulates
EP1273300A2 (de) Stabile Zubereitung auf Basis von Aspirin zur äusseren Anwendung
CA3105417A1 (en) A composition comprising a continuous aqueous phase, a discontinuous liquid oil phase and crisaborole
AU2020249807A1 (en) Fluorouracil-containing formulations
FR2569982A1 (fr) Composition anesthesique percutanee pour usage topique et son procede de preparation
CA2418008C (en) Antifungal ketoconazole composition for topical use
CA2247877A1 (en) Solubilizing delivery systems and method of manufacture
AU2001276567A1 (en) Antifungal ketoconazole composition for topical use
JPH0735330B2 (ja) 外用クリ−ム組成物
CN114681457B (zh) 丁丙诺啡透皮溶液及其制备方法和应用
US20140234430A1 (en) Pharmaceutical methods and topical compositions containing acitretin
EP1338276B1 (de) Adhäsive Zubereitung zur externen Anwendung
HU224686B1 (hu) Külsőleg alkalmazható, nimeszulidot tartalmazó gyógyszerkészítmény és eljárás előállítására
FI84696C (fi) Foerfarande foer framstaellning av en indometacininnehaollande salvakomposition.
CN118526456A (zh) 一种注射用液晶缓释组合物及其应用
WO2004073680A1 (ja) 液滴分散型軟膏剤
FI80608C (fi) Foerfarande foer framstaellning av lika stora partiklar av i vatten oloesliga organiska foereningar.
CN117379398A (zh) 一种胍法辛透皮贴剂及其制备方法
CN101605533B (zh) 制备固体非晶亚微米颗粒在水性介质中的稳定分散体的方法
Kadhum et al. Characterizations of Liquid Crystals as A Transdermal Drug Delivery System

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19930916

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU MC NL

A4 Supplementary search report drawn up and despatched

Effective date: 19960411

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU MC NL

17Q First examination report despatched

Effective date: 19960904

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

RBV Designated contracting states (corrected)

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU MC NL SE

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU MC NL SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 19990825

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19990825

Ref country code: ES

Free format text: THE PATENT HAS BEEN ANNULLED BY A DECISION OF A NATIONAL AUTHORITY

Effective date: 19990825

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 19990825

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 19990825

REF Corresponds to:

Ref document number: 183639

Country of ref document: AT

Date of ref document: 19990915

Kind code of ref document: T

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 69229857

Country of ref document: DE

Date of ref document: 19990930

ITF It: translation for a ep patent filed
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 19991125

ET Fr: translation filed
REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: BUGNION S.A.

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20000218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: THE PATENT HAS BEEN ANNULLED BY A DECISION OF A NATIONAL AUTHORITY

Effective date: 20000229

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: TRANSDERMAL TECHNOLOGIES PTY LIMITED

Free format text: COMMONWEALTH SCIENTIFIC AND INDUSTRIAL RESEARCH ORGANISATION#LIMESTONE AVENUE#CAMPBELL, ACT 2612 (AU) -TRANSFER TO- TRANSDERMAL TECHNOLOGIES PTY LIMITED#9 DIAMENTINA WAY LAURIETON#NEW SOUTH WALES (AU)

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20090225

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20090302

Year of fee payment: 18

Ref country code: CH

Payment date: 20090302

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20090226

Year of fee payment: 18

Ref country code: IT

Payment date: 20090225

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20090224

Year of fee payment: 18

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

EUG Se: european patent has lapsed
GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20100218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100228

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100228

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20101029

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100301

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100901

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100218

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100219